The Quest to Optimize Personalized Therapies for Cancer

A Conversation With Brian J. Druker, MD

In the late 1980s, Brian J. Druker, MD, was investigating the BCR-ABL tyrosine kinase as a target for therapeutic intervention for chronic myeloid leukemia (CML) in a laboratory at Dana-Farber Cancer Institute in Boston. By 1993, Dr. Druker had moved to Oregon Health & Science University in Portland, where he continued his research and found a compound called STI571 that could kill CML cells in vitro while preserving healthy cells. Five years later, Dr. Druker was conducting the first human clinical study of STI571, also known as imatinib mesylate (Gleevec).

In one early-phase clinical trial, imatinib had restored normal blood counts in 53 of 54 interferon-resistant CML patients, a response rate rarely achieved in cancer with a single agent. In March 2001, imatinib was granted a U.S. Food and Drug Administration (FDA) expedited review and approved 2 months later. Many of the patients in those early-phase clinical studies are alive today.

Dr. Druker’s research proved that it was possible to transform life-threatening cancers into manageable chronic diseases, a concept that is prevalent today but was largely unthinkable 15 years ago. His work in the development of targeted cancer therapies has resulted in numerous awards, including the American Cancer Society Medal of Honor, the Charles F. Kettering Prize from the General Motors Cancer Research Foundation, the Lasker-Debakey Award for Clinical Medical Research, the Ernest Beutler Prize from the American Society of Hematology and, most recently, the Taubman Prize for Excellence in Translational Medical Science and the Albany Medical Center Prize in Medicine and Biomedical Research.

The ASCO Post talked with Dr. Druker, Director of the Knight Cancer Institute at Oregon Health & Science University and JELD-WEN Chair of Leukemia Research, about his optimism for ending cancer and what is ahead in cancer therapies over the next decade.

Optimistic Outlook

In 2011, you gave a presentation called The End of Cancer Is Within Reach, in which you expressed optimism about the development of more effective targeted therapies for cancer. Why are you feeling so optimistic?

Twenty years ago, if you asked a lung cancer specialist for his prognosis on patients, he would have said we have no cures for patients with metastatic disease. Similarly, there were no cures for patients with metastatic breast cancer or metastatic melanoma.

Now, in lung cancer we have new agents like crizotinib (Xalkori) and erlotinib (Tarceva) that are producing rapid and dramatic responses in patients with metastatic disease. In melanoma, we are seeing Lazarus-like effects with the BRAF-targeted drugs vemurafenib (Zelboraf) and dabrafenib (Tafinlar). Unfortunately, we do see the rapid development of resistance to these drugs in the advanced metastatic setting.

What people are beginning to realize is that by targeting these genetic drivers of cancer, we’re seeing responses we thought were impossible 2 decades ago. And we are figuring out why patients become resistant to therapy, so instead of thinking about chemotherapy combinations like we have done for decades, we are starting to use combinations of rational therapies.

For example, in melanoma, when you combine dabrafenib with a MEK inhibitor, you get higher response rates with greater durability. To me, that’s really where we are headed. We are taking our understanding of the molecular drivers of cancer and the molecular basis of resistance, and we are seeing significant impacts.

Another example of a breakthrough drug is enzalutamide (Xtandi) for prostate cancer. It was approved by the FDA based on an understanding of why men become resistant to antiandrogen therapy, and it is prolonging survival more than any other drug in a decade for prostate cancer.

Those are the sorts of advances we are seeing, and that is why I am optimistic that this knowledge-based cancer therapy is going to be fundamentally different than what we have seen over the past 20 to 30 years.

Combination Strategies

Targeted therapies as single agents have not been effective in controlling cancer and usually have to be combined with conventional chemotherapies. Is there a smarter way of utilizing these drugs?

When I started along the path of developing [imatinib], people said single-agent therapy would never work; why bother investigating it? As it turns out, single-agent therapy does work; it just doesn’t have durability, so you could say the skeptics were right.

The way that I look at it is this: Don’t you want to combine active agents in your treatment regimens, and don’t you want to have a rationale for why you are combining these drugs instead of saying they have some activity and nonoverlapping toxicities? That’s what we did for 40 years of combination chemotherapy. Now we are saying we need to shut down specific pathways that the cancer requires for its growth and survival, and then we should be able to kill the cancer effectively and durably.

For now, we will continue to combine targeted therapies with conventional chemotherapies, but over the next 10 to 20 years, I suspect we will see a decrease in the number of chemotherapy drugs used and an increase in the number of combination targeted therapies used. In addition, we are likely to see combinations of the targeted therapies with immune therapeutics.

Controlled vs Cured

Many of the first CML patients treated with imatinib in clinical trials are still alive. Are those patients cured of their cancer?

Yes and no. Most people have to remain on active therapy, they take [imatinib] daily and they are fine. But what do you call that semantically? The general public may think of it as a cure, but most medical professionals would say, no, [imatinib] is an effective treatment but not a cure. I have been saying that the drug is an effective treatment that controls leukemia.

For CML patients on [imatinib] for 15 years and doing fine, if they consider it a cure, why should I be a stickler for semantics?

Current Focus

Please talk about your current research in leukemia.

We are investigating the targeting of specific molecular drivers in leukemia. We are also moving rapidly to test combinations of treatment, including targeted therapy with standard chemotherapy or combinations of targeted agents.

Our view is that we can bring genomic information into the clinic very rapidly, for example, in acute myeloid leukemia by targeting molecular drivers, understanding resistance mechanisms, and rapidly moving to combination therapy and showing that we can get higher response rates and greater durability. The goal is to move the cure rate from 30%, where it has been stuck for 40 years, to something significantly higher.

Looking Ahead

Will it be possible to cure various types of cancer, or will cancer become a chronic disease that is managed over a lifetime?

It would be a huge step forward if we could turn some of the metastatic cancers into manageable conditions. I would really like to see us move cancer therapy into the cure category, which means you get treatment for a fixed amount of time, the cancer is gone, you stop treatment, and the cancer doesn’t come back.

I am not sure whether that is a realistic goal over the next 10 years, but if you think about targeted cancer therapies, plus the immunotherapeutics that are being developed, it may in fact be possible. ■

Disclosure: Oregon Health & Science University has clinical trial contracts with Novartis to pay for patient costs, nurse and data manager salaries, and institutional overhead; however, Dr. Druker does not derive salary, nor does his laboratory receive funds, from these contracts.